Abstract Pancreatic cancer (PC) is the fourth leading causes of cancer-related deaths in both men and women and is one of the most lethal malignancies with a 5-year survival rate of ~8% and median survival duration of fewer than six months. Our long-term goal is that an understanding of the cellular and molecular mechanism(s) of the metastatic phenotype and pro-inflammatory/pro-angiogenic tumor milieu and its judicious manipulation can improve the treatment outcomes for PC patients. PC is frequently associated with oncogenic K-ras mutations (90-95%). Our preliminary data and published reports suggest that CXCR2 and its ligands regulate the behavior of tumor cells and recruitment of leukocytes, and endothelial (ECs) precursor cells. Limited literature exists on the role of Kras-driven CXCR2-dependent signaling in the de novo pathogenesis of PC. Thus, molecules driving a tumor-associated pro-inflammatory and pro-angiogenic phenotype have considerable potential as therapeutic targets, yet this area remains relatively under-explored in PC. To our knowledge, very little is known about the role of K-ras-driven CXCR2-dependent de novo PC development and impact of CXCR2 targeting in pancreatic cancer progression and metastasis. Our central hypothesis is that oncogenic Kras-induced expression of CXCR2 ligands plays a critical pro-tumorigenic role in inflammation-driven spontaneous tumorigenesis, angiogenesis and metastasis. A corollary to this hypothesis is that CXCR2 and its ligands are potential novel anti-tumorigenic and anti-metastatic therapeutic targets in PC. We will explore the role of CXCR2 and its ligands using xenogenic transplant models and autochthonous animal models (K- ras-driven) in PC pathology and develop a novel therapeutic strategy. To test our hypothesis, we will: 1) Define the mechanism by which K-ras-induced CXCR2 ligands expression promotes tumorigenesis and recruit pro- inflammatory and angiogenesis promoting precursor cells; and 2) Assess the therapeutic efficacy of targeting CXCR2-mediated mechanisms in pancreatic cancer treatment. Together, these studies will provide a mechanism for K-ras-dependent expression of CXCR2 ligands, delineate their role in PC pathobiology and assess their potential as therapeutic targets. With pharmacologic inhibitors of CXCR2 already in clinical trials for the treatment of inflammatory disorders, the rapid development of innovative cancer therapies targeting CXCR2 in combination with conventional anti-tumor regimens is a highly attractive option for making inroads in lethal PC. 1